The overall goal of this project is to determine the cellular interface where TCR gamma/delta cells participate in the systemic immune response to a model protein antigen, Ovalbumin (OVA). They have striking results that TCR gamma/delta cells are potent contributors to the T- and B-cells systemic immune response to OVA from our studies using a mouse model of asthma. Ovalbumin-challenged wildtype mice demonstrate marked allergic inflammatory response, evidenced by airway eosinophilia and elevated serum IgE. These responses are attenuated in TCR gamma -/- animals and completely absent in TCR beta-/- mice. Airway responsiveness to aerosolized methacholine is also reduced in challenged TCR6-r animals relative to challenged wildtype mice. This is true for mice lacking TCR gamma/delta cells throughout life, or in wildtype mice that are depleted of TCR gamma/delta cells only during the recall response to aerosol challenge. The application proposes that TCR gamma/delta cells function in the systemic immune response to OVA (administered i.p. with Alum) by promoting differentiation of CD4+ TCR alpha/beta cells. These OVA-specific CD4 + cells then promote B-cell differentiation and immunoglobulin class-switching. The visualization and enumeration of these events will suggest possible sites and molecular events whereby TCR gamma/delta cells can affect the immune response. The observations that TCR gamma/delta cells continue to impact on the magnitude of the cellular and humoral response following 2 or 3 immunization or challenges are more perplexing in light of what is known regarding the behavior of memory CD4+ TCR alpha/beta cells and B lymphocytes. This could imply that TCR gamma/delta cells are specific for OVA and that, like TCR alpha/beta B-cells, they exhibit functional memory responses. Alternatively, TCR gamma/delta cells have the same response to OVA upon each exposure, and the functional impact of that response is manifested in the same way irrespective of whether it occurs during the primary or recall response to antigen. These studies represent one of first model systems where all the reagents necessary have been assembled to begin to define the role of TCR gamma/delta cells in a "conventional" immune response. Specifically, they propose to: AIM 1. Determine the impact of TCR gamma/delta cells on commitment of CD4+ TCR alpha/beta cells to the Th2 lineage. AIM 2. Determine the impact of TCR gamma/delta cells in B-cell production of OVA-specific Ig. AIM 3. Determine if TCR gamma/delta T-cells represent innate or adaptive components of the systemic immune response to OVA.